Endothelins (ET's) are endothelium-derived vasoconstrictor peptides produced and released by vascular endothelial cells upon various physical and chemical stimuli. We investigated 1) the urinary excretion and plasma levels of ET in control rats and rats pretreated with the neutral endopeptidase inhibitor (NEP-1) SQ29,072. 2).The effects of NEP-1 on the fate of infused 125-I-ET using high performance liquid chromatography. 3) The effect of either bilateral nephrectomy or administration of NEP-1 on the depressor activity or infused ET. NEP-1 (30 and 60 ng/kg) significantly increased the urinary excretion of endothelin at 30, 60 and 90 minutes. In addition, the higher dose of NEP-1 elevated plasma levels of ET by 55%. After the infusion of 125-I-ET into control rats, the recovery of radioactivity in the urine was negligible, while in the presence of NEP-1, radioactivity increased 3 fold. Furthermore, analysis of the recovered radioactivity by HPLC revealed that intact ET comprised 6-9% of the total counts in control rats, while in rats pretreated with the inhibitor that value increased to 50-60%. Bilateral nephrectomy was associated with potentiation and prolongation of the hypertensive effect of administered ET. Inhibition of NEP potentiated the depressor activity of ET in a manner similar to that obtained in bilateral nephrectomized rats.